1. Field of the Invention
The present invention relates to novel hydroxamic acid compounds which inhibit the enzyme, 5-lipoxygenase. The metabolism of arachidonic acid via 5-lipoxygenase gives rise to products implicated as mediators in certain inflammatory and allergic disease states. Inhibition of 5-lipoxygenase blocks the production of such mediators and alleviates the inflammatory and allergic conditions resulting therefrom.
2. Description of the Prior Art
The literature reveals a large number of hydroxamic acid derivatives, some of which possess lipoxygenase-inhibitory activity and/or pharmaceutical activities associated with inhibition of lipoxygenase enzymes.
At the Gordon Conference in Medicinal Chemistry held July 28-Aug. 1, 1986 in New London, N.H. a handout was distributed disclosing, inter alia, compounds of the formula ##STR2## as 5-lipoxygenase inhibitors. Biological data was provided for phenylalkylhydroxamic acids of the formula ##STR3## where n=0, 1, 2 or 3, but no mention was made of compounds with longer alkyl groups such as the n=6-11 compounds of the present invention. These compounds were also disclosed at the 1986 Fall American Chemical Society Meeting Sept. 8, 1986-Sept. 12, 1986) in Anaheim, Calif.
Japanese Kokai No. 59/46244 in the name of Nissan Chemical Co. discloses hydroxamic acid derivatives of the formula EQU AB(CH.sub.2).sub.n CONHOH
where
A is RX.sub.m in which PA1 R is phenyl, pyrrolyl, thienyl, imidazolyl or thiazolyl; PA1 X is halogen, lower alkyl, lower alkoxy or nitro; PA1 m is 0, 1, or 2; PA1 the X substituents may be the same or different; PA1 B is --CHOH--, --CH.sub.2 --, --O-- or ;13 CO-- and n=2-10 as anti-protozoal agents. The only compound disclosed where B is --CH.sub.2 -- and A is phenyl is the compound of the formula ##STR4## There is no mention of lipoxygenase-inhibitory activity. Applicants have tested the corresponding unsubstituted phenyl compound of the formula ##STR5## in the 5-lipoxygenase inhibition test reported in the text below and have found such compound to have an IC.sub.50 (.mu.M) of &gt;100 compared with an IC.sub.50 value of 20.9 for the compound of the present invention having the formula ##STR6## PA1 A is H, aryl, lower alkyl, aryl-lower alkyl or heteroaryl; and PA1 B is ##STR16## n=0-6, wherein D is H, CONR.sub.3 R.sub.4, CO.sub.2 H, CO.sub.2 R.sub.5, CH.sub.2 OH or CH.sub.2 OR.sub.6, PA1 R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are independently H, lower alkyl, aryl, aryl-lower alkyl or heteroaryl; PA1 E is H, OH, lower alkyl, aryl or heteroaryl; and PA1 F is ##STR17## in which G is the same as R.sub.1 and R.sub.2. The present compounds may be distinguished by the presence of a hydroxamic functional group which has been found necessary for good activity. PA1 n is 0 or 1 and m is 0, 1, 2 or 3; but n and m are not 0 simultaneously; PA1 R.sub.1 and R.sub.2 independently are H, C.sub.1 -C.sub.6 alkyl, and electron-withdrawing group or R.sub.4 ; PA1 R.sub.3 is H, C.sub.1 -C.sub.6 alkyl or cycloalkyl, or R.sub.4 ; and PA1 R.sub.4 at each occurrence, has the formula ##STR19## where Y is hydrogen or an electron-withdrawing group; and wherein M is a pharmaceutically acceptable cation, as lipoxygenase inhibitors. Among the compounds designated as Ex. Nos. 18 and 19 are those of the formula ##STR20## These compound may be distinguished from the present compounds by the presence of a naphthyl instead of a phenyl group and a shorter alkyl chain. PA1 R and R.sub.1 are ach independently hydrogen, lower cycloalkyl, fused cycloalkyl or lower alkyl-substituted fused cycloalkyl, lower alkyl, phenyl, naphthyl or a nitrogen, oxygen or sulfur heterocyclic ring or heterocyclic-lower alkyl; PA1 Z, Z.sub.1 and Z.sub.2 are each a chemical bond or an alkylene chain or a mono- or disubstituted alkylene chain containing up to 6 carbon atoms in the principal chain and up to a total of about 10 carbon atoms, a lower cycloalkyl, a nitrogen, oxygen or sulfur heterocyclic ring or heterocyclic lower alkyl, or a mono- or di-substituted lower cycloalkyl or heterocyclic lower alkyl; PA1 X and Y are each independently O, S, CR.sub.3, R.sub.4 or a chemical bond; PA1 R.sub.3 and R.sub.4 are each independently H or lower alkyl; each R.sub.5 is H, aryl, lower alkarayl, formyl, nitro, cyano, amino, lower aminoalkyl, lower alkylamino, lower aralkylamino, halo, trihalo alkyl, carbamoyl or aroyl; PA1 n is an integer from 0-2; and PA1 n.sub.1 is an integer from 1-2. By judicious selection of the appropriate variables, one can obtain compounds of the formula ##STR24## where n can be up to seven carbons in length. However, Z.sub.1 is preferably only up to three carbon atoms in length, thus making the preferred compounds of the above formula those with n.ltoreq.4. The lack of any specific disclosure of longer chain compounds together with the disclosed preference for n.ltoreq.4 teaches away from applicants' compounds having n=6-11.
European Patent Application No. 161,939 discloses substituted benzohydroxamic acids of the formula ##STR7## where, inter alia, R.sup.1 and R.sup.2 may be hydrogen, as lipoxygenase inhibitors. They may be distinguished from the present compounds by the lack of a carbon chain between the phenyl ring and the hydroxamic function.
K. Tanaka, et al. in Chem. Pharm. Bull. 31: 2810-2819, 1983, disclose some substituted phenylpropionohydroxamic acids of the type ##STR8## which are reported to have antiinflammatory activity. These compounds are distinguished from the present compounds by having a shorter alkyl chain length which has been found to be inappropriate for good activity.
U.S. Pat. No. 4,564,476 discloses a series of lipoxygenase inhibitors of the general formula ##STR9## in which, inter alia, R.sub.1, R.sub.2 and R.sub.3 may by hydrogen, X is O or CH.dbd.CH and Y may be --CONHOH. The compounds may be distinguished from the present compounds in that (1) they must have at least one double bond plus one heteroatom or at least two double bonds in the sidechain and (2) there is no specific disclosure of compounds having the hydroxamic acid group.
E. J. Corey et al. in J. Amer. Chem. Soc. 106: 1503-1504, 1984, discloses the compound ##STR10## as a lipoxygenase inhibitor. This compound may be distinguished from the present compounds by the presence of the double bond in the sidechain.
U. S. Pat. No. 3,328,138 generically discloses hydroxamic acids of the formula ##STR11## where, inter alia, R may be alkyl substituted by aryl, the entire radical having from 7-28 carbon atoms, as motor fuel additives.
U.S. Pat. No. 3,479,396 discloses compounds of the formula ##STR12## where R and R.sup.1 can be alkyl, cycloalkyl, alkyloxy, alkenyloxy, cycloalkenyloxy, alkylthio, cycloalkyloxy, cycloalkylalkyloxy or arylalkyloxy; R.sup.1 can also be hydrogen, and n is an integer of 0 to 2 as having antipyretic, antiinflammatory, antispasmodic and analgesic properties. These compounds have only one carbon atom in the alkyl chain.
U.S. Pat. No. 4,188,338 discloses, inter alia, ring-substituted compounds of the type ##STR13## where R is alkoxy, alkenyloxy, alkyl or benzyloxy, R.sub.1 and R.sub.2 are H, alkoxy, alkenyloxy, benzyloxy or alkyl and n=2-3 as having inhibitory activity against blood platelet aggregation. In the specification (column 1, lines 20-60) it is stated that as the chain length increases the antiinflammatory activity decreases and that the disclosed compounds specifically have no antiinflammatory activity (column 2, lines 43-50). This leads away from expecting potent antiinflammatory activity in compounds where n is .gtoreq.2 such as those of the present invention where n=6-11.
Japanese Pat. No. 61/33,115 discloses a series of naphthloxyalkyl hydroxamic acids of the formula ##STR14## as antiinflammatory agents. These compounds may be distinguished from the present compounds by the presence of the oxygen atom in the sidechain and a naphthyl instead of a phenyl group.
U.S. Pat. No. 4,579,866 (equivalent to Japanese 61/00054) discloses 5-lipoxygenase inhibitors of the formula ##STR15## where R.sup.1 and R.sup.2 are independently H, OH, lower alkyl, lower alkoxy, aryloxy, heteroaryloxy, heteroaryl lower alkoxy, aryl, heteroaryl, aryl-lower alkyl, aryl-lower alkoxy, halogenated aryl-lower alkoxy, lower alkenyl, lower alkynyl, lower alkenyloxy, lower alkynyloxy, halogen or trifluoromethyl;
wherein
U.S. Pat. No. 4,608,390 discloses compounds of the formula ##STR18## where X is H, C.sub.1 -C.sub.22 alkyl or alkenyl, or an electron-withdrawing group;
U.S. Pat. No. 4,605,669 discloses lipoxygenase-inhibiting naphthohydroxamic acids of the formula ##STR21## where R.sup.1 is H or C.sub.1 -C.sub.6 alkyl; R.sup.2 is C.sub.1 -C.sub.22 alkyl, cycloalkyl, aralkyl or alkenyl; and M is a pharmaceutically acceptable cation. These compounds have naphthyl instead of phenyl and have no alkyl chain.
European Patent Application 199,151 A2 discloses lipoxygenase-inhibiting compounds of the formula ##STR22## where R.sub.1 is trinuclear aromatic or biaryl group; R.sub.2 is hydrogen or C.sub.1 -C.sub.6 alkyl or cycloalkyl; n is 0 or 1; and M is a pharmaceutically acceptable cation. Again, these compounds do not have a phenyl group in the sidechain and have either no alkyl chain or a double bond in the chain.
European Patent Application No. 196,674 discloses lipoxygenase-inhibiting hydroxamate compounds of the formula ##STR23## where R.sub.2 is H, lower alkyl, formyl or C.sub.2 -C.sub.10 alkanoyl;
Despite the disclosure in the literature of various 5-lipoxygenase-inhibiting compounds as illustrated above, there is a need for more potent inhibitors of this enzyme.